Neuromonitoring is a subfield of clinical patient monitoring focused on measuring various aspects of brain function and on changes therein caused by drugs commonly used to induce and maintain anesthesia in an operation room or sedation in patients under critical or intensive care.
Electroencephalography (EEG) is a well-established method for assessing brain activity. When measurement electrodes are attached on the skin of the skull surface, the weak biopotential signals generated in the pyramid cells of the cortex may be recorded and analyzed. The EEG has been in wide use for decades in basic research of the neural systems of the brain as well as in the clinical diagnosis of various central nervous system diseases and disorders.
Electromyography (EMG) is a method for recording electrical biopotentials of muscles. In an EMG measurement, the electrodes are attached onto the surface of the skin overlying a muscle. When a biopotential signal is recorded from the forehead of a subject, the recorded signal indicates both the activity of the facial muscles (fEMG) and the brain (EEG).
One of the special applications of the EEG, which has received attention recently, is the use of a processed EEG signal for objective quantification of the amount and type of brain activity for the purpose of determining the level of consciousness of a patient. In its simplest form, the utilization of an EEG signal allows the automatic detection of the alertness of an individual, i.e. if he or she is awake or asleep. This has become an issue of increased interest, both scientifically and commercially, in the context of measuring the depth of unconsciousness induced by anesthesia during surgery.
Another important component of balanced anesthesia is analgesia which means prevention of pain reactions of a patient by administration of pain medication. Adequate analgesia reduces surgical stress and there is firm evidence that it decreases postoperative morbidity. Awareness during surgery with insufficient analgesia may lead to a post-traumatic stress disorder. Low quality pre- and intra-operative analgesia makes it difficult to select the optimal pain management strategy later on. More specifically, it may cause exposure to unwanted side effects during the recovery from the surgery. If the anesthesia is too light and involves insufficient hypnosis, it may cause traumatic experiences both for the patient and for the anesthesia personnel. From an economical point of view, if the anesthesia is too deep, it may cause increased perioperative costs through extra use of drugs and time, and extend the time required for post-operative care.
Virtually every patient being cared for in an Intensive Care Unit, for example, receives some form of sedation. However, the control of the depth of the sedation administered to a patient is still problematic, and therefore oversedation and undersedation are both common occurrences in intensive care units. At present, monitoring the level of sedation is mainly handled by using subjective observations from the patient. Various sedation assessment scales have been developed for subjectively assessing the level of sedation, the Ramsay Score being one of the most widely used tools for this purpose. Inappropriate sedation can lead to an adverse clinical outcome and reduce treatment efficacy in critical care settings. Oversedation may cause various complications, such as cardiovascular instability, and it may also increase the length of stay in the hospital and prolong the usage time of expensive facilities, such as the intensive care unit. Undersedation, in turn, may result in patient anxiety and agitation, which can further interfere with care, especially with that of neurological patients, and result in harm to the patient and the nursing staff.
In connection with anesthesia, the patient is administered hypnotic, analgesic, and neuromuscular blocking agents. However, a certain drug is not normally a pure hypnotic or a pure analgesic, but the drugs normally have additive effects. The anesthetics, i.e. drugs used to produce anesthesia, may also be divided into different groups according to the site of their action. This is discussed briefly in the following.
Glutamate is the most important excitatory transmitter in the central nervous system. Glutamate is involved in sensory processing, motor control, and higher cortical functions, including memory and learning. Glutamate acts both through ligand gated ion channels (ionotropic receptors) and second messenger (here G-protein) coupled (metabotropic) receptors. Ionotropic glutamate receptors can be divided into three groups: AMPA receptors, NMDA receptors, and kainate receptors.
Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system. GABA is involved in 20 to 50 percent of brain synapses, depending on the brain area. There are three types of GABA receptors: GABAA and GABAC receptors, which are associated with chloride channels, and GABAB receptors, which are G-protein coupled (metabotropic) receptors. Binding of GABA to a GABAA receptor increases the permeability to chloride ion, which leads to hyperpolarization of the neuronal membrane and to increased inhibition. A GABAA receptor contains, for example, the following binding sites: GABA, benzodiazepine and barbiturate sites.
Anesthetics bind to specific, saturable binding sites (i.e. receptors) typically on the cell membrane. Effects of anesthetics are receptor-mediated. General anesthesia may be produced by different mechanisms: anesthetics may act at different receptors or they may act at different sites of the same receptor.
At present, most of the anesthetics act primarily through GABAA-receptors. These drugs, also termed GABA agonistic agents, potentiate the actions of GABA causing hyperpolarization of the neuronal membrane. This action is common to barbiturates, propofol, etomidate, and steroid anesthetics, for example, and probably also to inhalational anesthetics.
Although most anesthesias are today conducted by GABA agonistic agents, another group of anesthetics is also used, which affects the N-methyl-D-aspartate (NMDA) receptors thereby attenuating excitatory neurotransmission. These drugs, also termed NMDA antagonists in this context, inhibit the actions of glutamate by blocking the NMDA receptors. This action is common to phencyclidine derivatives, like ketamine and S-ketamine, and to nitrous oxide and xenon, for example.
In addition to the EEG signal data, EMG signal data obtained from facial muscles (fEMG) of the forehead is used for monitoring purposes during anesthesia and intensive care. Recovering facial muscle activity is often the first indicator of the patient approaching consciousness. When this muscle activity is sensed by electrodes placed appropriately, it provides an early indication that the patient is emerging from anesthesia. Similarly, these electrodes can sense pain reactions when the anesthesia is not adequate due to inadequate analgesia. So, the EMG signals give an early warning of arousal and may also be indicative of inadequate analgesia.
An objective tool for assessing the level of anesthesia or sedation is disclosed in U.S. Pat. No. 6,801,803, which depicts a method and device for ascertaining the cerebral state of a patient. In this disclosure, a measure derived from EMG signal data enhances and confirms the determination of the hypnotic state made using EEG signal data. As the EMG data may be computed more frequently than the EEG data, it follows changes in the hypnotic state of the patient more rapidly. The combined indicator provided by the EEG signal data and EMG signal data may also be used for assessing the adequacy of anesthesia or the level of sedation.
At present, the processes utilizing raw EEG signal data for monitoring a patient under sedation or anesthesia utilize the fact that the frequencies of the EMG spectrum are above the frequencies of brain activities, whereby the EMG components can be separated by methods of signal processing or spectral analysis from the EEG signal components contained in the signal data. This causes no problems with the use of GABA agonistic agents, since the administration of GABA agonistic agents results in a more ordered EEG signal with spectral power concentrated onto the low frequencies. In this context, low frequencies refer to frequencies below about 20 Hz, while high frequencies refer to frequencies above about 20 Hz. A more ordered EEG signal will be the result also when NMDA antagonists are administered. However, NMDA antagonists produce both low and high frequency EEG activity, which confuses the operation of the present-day algorithms, since they cannot anymore separate high frequency EEG activity from EMG activity. Therefore, the level of hypnosis (or the depth of anesthesia) measured by such algorithms may not be reliable if high frequency EEG activity is induced.
The present invention seeks to alleviate or eliminate the above-mentioned drawback and to bring about a method by means of which the anesthetic state of a subject may be evaluated more accurately whenever drugs inducing high frequency EEG activity are used.